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Résumé: Les bactéries peuvent résister aux antibiotiques par exportation active grâce à des transporteurs membranaires appelés pompes d’efflux. Ces protéines sont spécifiques d’une classe d’antibiotiques ou au contraire responsables de MDR (multidrug resistance). Pour fonctionner, les pompes d’efflux utilisent l’énergie fournie par dissipation d’un gradient de protons (familles MFS, RND et SMR) ou d’ions sodium (famille MATE) ou encore par hydrolyse d’ATP (famille ABC). Plusieurs fonctions physiologiques ont été décrites chez les procaryotes, comme la protection vis-à-vis de toxiques environnementaux et le maintien de l’homéostasie cellulaire, qui contribuent indirectement à la virulence bactérienne. Chez les bactéries à Gram négatif, les systèmes d’efflux sont souvent des complexes protéiques ternaires avec une pompe transmembranaire, une protéine périplasmique de jonction et une porine de la membrane externe. Les pompes les plus fréquemment rencontrées sont de type RND comme AcrB chez Escherichia coli ou MexB chez Pseudomonas aeruginosa. Chez les bactéries à Gram positif, les systèmes d’efflux ne sont constitués que de la pompe. Les plus étudiés sont les pompes MFS comme NorA ou QacA chez Staphylococcus aureus et PmrA chez Streptococcus pneumoniae. Quelques transporteurs ont aussi été décrits chez les mycobactéries. Malgré la caractérisation d’un nombre croissant de pompes, les conséquences cliniques de la résistance par efflux sont mal connues du fait de niveaux variables d’expression et du manque de marqueurs spécifiques pour les détecter en routine. Enfin, l’utilisation d’inhibiteurs spécifiques des pompes bactériennes semble constituer une approche thérapeutique intéressante, cependant difficile à mettre en pratique, en raison de leur toxicité pour les cellules eucaryotes. [Copyright &y& Elsevier]

Antibiotic resistance in Gram-positive bacteria already has a significant impact on morbidity and mortality. The situation is particularly alarming in the case of methicillin-resistant Staphylococcus aureus and glycopeptide-resistant Enterococcus faecium, which have shown an ability to spread to new ecological niches and to generate new clones with both increased drug resistance and increased virulence. The potential for genetic exchanges between these two species raises the specter of highly resistant and virulent S. aureus strains.

Enterococci are responsible for various community- and hospital-acquired infections. Glycopeptides (vancomycin and teicoplanin) are active against these microorganisms by inhibiting cell wall synthesis through binding to cell wall precursors. Enterococcus faecium has developed multidrug resistance, including resistance to glycopeptides. Resistance to glycopeptides is due to the acquisition of an operon of genes cooperating to synthesize precursors devoid of affinity for the glycopeptides. Outbreaks were recently reported in hospital settings. These outbreaks were due to E. faecium isolates belonging to an hospital-adapted clonal complex (CC17) characterized by high level resistance to ampicillin and fluoroquinolones and frequently containing virulence factors. Outbreaks may be controlled by appropriate measures and new antibiotics are available in therapy. However, spreading of clonal strains adapted to hospitals require close surveillance.

Bacteria can resist to antibiotics by active exportation mediated by membrane transporters called efflux pumps. These proteins can be specific of a class of antibiotics or responsible for multidrug resistance (MDR). Energy required by efflux pumps can be provided by transmembrane electrochemical gradient of protons (MFS, RND, SMR families) or sodium ions (MATE family) or by ATP hydrolysis (ABC family). Several physiological functions have been described in prokaryotes, such as protection from environmental toxics and regulation of cell homeostasis, which can indirectly contributes to bacterial virulence. In Gram-negative bacteria, efflux transporters usually are organized as multicomponent systems in which the efflux pump located in the inner membrane works in conjunction with a periplasmic fusion protein and an outer membrane factor. The most frequently encountered pumps are of the RND-type such as AcrB in Escherichia coli or MexB in Pseudomonas aeruginosa. In Gram-positive bacteria, efflux is solely mediated by the pump protein, so described with MFS pumps such as NorA or QacA in Staphylococcus aureus and PmrA in Streptococcus pneumoniae. Efflux transporters have also been described in mycobacteria. Although numerous bacterial pumps have been characterized, the clinical consequences of efflux-mediated resistance are mostly unknown because of variable levels of expression and of the lack of specific markers in laboratory practice. Finally, associating pump-specific inhibitors to efflux-sensitive antibiotics might prove an interesting therapeutic perspective. However, inhibitors that are not toxic to eukaryotic cells remain to be identified.